Inflammasomes are protein complexes that facilitate the maturation and secretion of the pro-inflammatory cytokines interleukin (IL) -1 and IL-18, which are important for innate immune responses. Nevertheless, for maintaining homeostasis balance and temporary inflammasome activation is essential, since uncontrolled and excessive cytokine production has been linked to rheumatic and other inflammatory diseases. The first step of inflammasome activation is the sensing of pathogens and cellular danger signals by pattern recognition receptors (PRRs) and the NOD-like receptor containing a pyrin domain (NLRP) 3 is one of them. Upon activation, NLRP3 recruits the adaptor ASC and the effector caspase-1, which subsequently processes IL-1 and IL-18 into their biologically active forms. However, recently the mitochondrial MAVS protein has been proposed to also function as an inflammasome adaptor and caspases-11 and -8 were implicated as alternative effectors for NLRP3 inflammasomes during bacterial infections. Nevertheless, their contribution and relevance to NLRP3 inflammasome activation in rheumatic and inflammatory diseases has not been investigated yet. The proper function of NLRP3 is crucial for human health, since defects in the NLRP3 inflammasome regulation are associated with several inflammatory diseases, including Cryopyrinopathies and crystal arthropathies. While hereditary mutations render NLRP3 constitutively active in Cryopyrinopathies, an excess of danger signals in the form of monosodium urate (MSU) crystal precipitates in the joint triggers NLRP3 inflammasome activation and an acute local inflammatory response that causes gouty arthritis. Hence, in both diseases the uncontrolled activation of NLRP3 leads to excessive IL-1 production. Consequently, blocking IL-1 improves disease symptoms and patient outcomes. However, IL-1 is crucial for innate immune responses and elimination of IL- 1 altogether can also impair host defense. Thus, it is crucial to gain a detailed understanding of the NLRP3 inflammasomes regulation in Cryopyrinopathies and crystal arthropathies in order to develop specific NLRP3 inflammasome targeted therapies. I propose to study the function of MAVS and caspases-11 and -8 in NLRP3 inflammasome linked Muckle-Wells syndrome (MWS), which is a Cryopyrinopathy, and MSU crystal-induced gout by utilizing in vivo mouse models. I expect that the results from this study will have widespread implications for future therapies of MWS and gout but also for other NLRP3-associated diseases and will concurrently contribute to a better understanding of the complex molecular mechanisms involved in NLRP3 inflammasome biology. My long-term career goal is to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic and inflammatory diseases. I belief that this proposal is an ideal training vehicle for a K01 Mentored Scientist Development Award, as I will become proficient in mouse models of rheumatic and inflammatory diseases, as well as translational immunology, thereby developing my own niche as I begin to establish an independent academic career.
Inflammatory diseases such as cryopyrinopathies, and crystal arthropathies are caused by the overproduction of the pro-inflammatory cytokine Interleukin-1beta (IL-1? which is regulated in activation complexes called inflammasomes. While current therapies rely on the systemic removal of IL-1?, targeting the inflammasome would be much more beneficial, since IL-18, another proinflammatory cytokine processed by the inflammasome, has been shown to also contribute to inflammatory diseases. Therefore, by characterizing the contribution of novel inflammasome components to inflammatory diseases, new approaches in the development of safe and effective anti- inflammatory drugs will be possible and our knowledge of how inflammasomes are regulated during inflammatory diseases will significantly advance.
|Chu, Lan H; Indramohan, Mohanalaxmi; Ratsimandresy, Rojo A et al. (2018) The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat Commun 9:996|
|Indramohan, Mohanalaxmi; Stehlik, Christian; Dorfleutner, Andrea (2018) COPs and POPs Patrol Inflammasome Activation. J Mol Biol 430:153-173|
|Tsai, FuNien; Homan, Philip J; Agrawal, Hemant et al. (2017) Bim suppresses the development of SLE by limiting myeloid inflammatory responses. J Exp Med 214:3753-3773|
|Ratsimandresy, Rojo A; Chu, Lan H; Khare, Sonal et al. (2017) The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation. Nat Commun 8:15556|
|Shi, Bo; Huang, Qi-Quan; Birkett, Robert et al. (2017) SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages. Autophagy 13:285-301|
|Ratsimandresy, Rojo A; Indramohan, Mohanalaxmi; Dorfleutner, Andrea et al. (2017) The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway. Cell Mol Immunol 14:127-142|
|Khare, Sonal; Radian, Alexander D; Dorfleutner, Andrea et al. (2016) Measuring NLR Oligomerization I: Size Exclusion Chromatography, Co-immunoprecipitation, and Cross-Linking. Methods Mol Biol 1417:131-43|
|de Almeida, Lucia; Dorfleutner, Andrea; Stehlik, Christian (2016) In vivo Analysis of Neutrophil Infiltration during LPS-induced Peritonitis. Bio Protoc 6:|
|de Almeida, Lucia; Dorfleutner, Andrea; Stehlik, Christian (2016) ASC-particle-induced Peritonitis. Bio Protoc 6:|
|Dorfleutner, Andrea; Stehlik, Christian (2016) A dRAStic RHOAdblock of Pyrin inflammasome activation. Nat Immunol 17:900-2|
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